BEIJING, Feb. 20, 2020 /PRNewswire/ -- In a campaign to screen drugs for the treatment of
COVID-19, the disease caused by SARS-CoV-2, StoneWise, a company specialized in applying
artificial intelligence to innovative drug design solutions for
innovative drug R&D enterprises and institutions, has conducted
research and been sharing the electronic structure data of more
than 1400 nucleoside inhibitors against various RNA polymerases
from patents up to February 5,
2020. Using its proprietary AI-driven drug design platform,
StoneWise has ranked dozens of nucleosides from these molecules as
potential inhibitors against SARS-CoV-2 RNA polymerase.
StoneWise hereby makes all the related data freely available to
the scientific community for further research and development. The
download links are enclosed at the end of this article.
Furthermore, StoneWise and Institute of Materia Medica, Chinese Academy of Medical
Sciences and Peking Union Medical College have reached a strategic
research collaboration in the COVID-19 treatment. StoneWise will
use its state-of-the-art AI-based drug discovery technology and
graph-extraction algorithm in the collaboration to expedite the
progress.
Sharing of structure data of more
than 1400 RNA polymerase nucleoside inhibitors from
patents
The National Medical Products Administration (NMPA) of
China has swiftly approved several
clinical trial applications for the treatment of COVID-19 recently,
in which much hope is being rest on Remdesivir (GS-5734) due to its
broad spectrum anti-RNA polymerases (RdRp) activities, the
promising efficacy against SARS, MERS and Ebola viruses in pilot
studies, and its safety profile in clinical trials so far [1-3].
The primary sequence alignment of SARS-CoV-2 nsp 12 (Gene Bank code:YP_009725307.1) and SARS-CoV nsp
12 (PDB code: 6NUR_A) by Blast test [4-5] indicates the identity of
the two sequences is up to 96%, and is completely identical in the
NTP-binding domains (the domains 612-626, 678-688 and 758-763 of
SARS-CoV-2 nsp 12). This lays scientific foundation for the
argument that RdRp-targeted drugs from other virus infectious
diseases have the potential for COVID-19 treatment.
We expect Remdesivir (GS-5734) become a promising treatment
against the COVID-19 in the near future. However, the SARS-CoV-2 is
not exactly the same as SARS, MERS or Ebola viruses. Its
micro-environment may demand different drug properties, and its
drug resistance may also differ from other viruses. Therefore,
RdRp inhibitors with distinct property profiles against SARS-CoV-2
are deemed necessary to develop. In the past decades, humans have
synthesized many small-molecule nucleosides as RdRp inhibitors
against various viruses, and the efficacy and toxicity for some of
the molecules have been extensively studied in many laboratories.
These molecules, including GS-5734, share similar fundamental
structural features and pharmacophores against RdRp, and therefore
they are most likely to become the potential high-value compound
library to discover the better "fit" molecules specific to
SARS-CoV-2. These molecules should be studied more deeply in a
wider scope for SARS-CoV-2.
In this study, StoneWise retrieved more than 50 patents related
to nucleoside-based RNA polymerase inhibitors (including the
GS-5734 and its analogs developed by Gilead), and obtained more
than 1400 compounds using StoneWise's AI-based graph-extraction
algorithm in combination with manual annotation for structure
extraction and processing.
Note: The structure data provided herein is derived from the
keyword-based patent search, so mistakes and data missing are
inevitable. The data is for reference of scientific research use
only.
Potential application of RNA polymerase nucleoside inhibitors
in inhibiting the SARS-CoV-2 RNA polymerase
After obtaining these embodiment compounds, StoneWise has
conducted series of research and discovered dozens of nucleoside
molecules including GS-573 parent drug structure to have potential
inhibiting effect against the SARS-CoV-2 RNA polymerase. Details of
small molecule processing, SARS-CoV-2 RNA polymerase homologous
modeling, virtual screening, MD simulation and the AI-based
proprietary compound screening technologies are in the experimental
methods section at the end of this article. Limited by the size of
this article, only some representative molecules are shown
here.
The above molecules have been studied for anti-viruses, anti-flu
and anti-HCV applications, including some basic research of
druggability using prodrug strategy. Their synthetic accessibility
has been validated and this will expedite the development phase if
these molecules have been selected for further studies.
StoneWise is keen to make some contribution to the fundamental
research for COVID-19 treatment via sharing our research progress
and relevant data. Only with the fundamental research mature
enough, can we have more robust and sufficient response strategy
for the current and future epidemic outbreak.
Thanks for all the project members of their devotion to this
research. Specifically we thank Prof. Liu Zhenming of Peking
University for his support and assistance for this project.
Appendix: Introduction to the Experimental Methods
- Protein homologous modeling
Prior to protein homology modeling, HMM-HMM was used in the
homologous multiple sequence alignment analysis based on SARS nsp
12 (PDB code: 6NUR_A) and Norwalk RdRp structure (3BSO).
Taken 6NUR_A as a template, we constructed the initial
SARS-CoV-2 RdRp 3D structure through single point mutation
method referring to the primary sequence difference in the SARS nsp
12 (PDB code: 6NUR_A) and the SARS-CoV-2 RdRp (Gene Bank code: YP_009725307.1). In the initial
SARS-CoV-2 RdRp structure's NTP binding domains 612-626,
678-688 and 758-763, we constrained the corresponding conformation
at the CTP binding site of the 3BSO, and constrained the chelation
configuration of Mn2+ ion with the key amino acid
residues of SARS-CoV-2 RdRp (D618, Y619, D761 and D760). For the region of RNA model
& primer binding domains of the COVID-19 RdRp, we constrained
the conformation in the double-stranded RNA binding domains of the
3BSO. During the modeling, we retained the RNA, metal ions and key
solvent molecules in the 3BSO. At the end of the modeling, the C515
of the mutated RNA chain was U, G and A respectively, and four
models including C were obtained.
For the molecular docking, the triphosphoryl portion of GS-5734
was forced to maintain the correct chelation configuration with the
Mn2+ ion, while the remaining portion was allowed
to move freely. The SARS-CoV-2 RdRp (U) and GS-5734 complex
obtained by docking is used for the molecular dynamics simulation
in the next step.
- Molecular dynamics simulation
The SARS-CoV-2 RdRp (U) -GS-5734 complex is subject to
parameterization, solvation and charge balance in the Charmm-GUI,
and subsequently undergone a short NPT simulation at 600ps for
complex energy optimization and hydrogen bond optimization. The
resultant stable conformation from the simulation was selected for
the subsequent docking/virtual screening operation.
The aforementioned 1400 compounds retrieved from patents were
pre-processed by eliminating the prodrug functional moieties in the
embodiment compounds and triphosphorylating the 5-CH2-OH
at ribose to create final list of molecules for virtual
screening. 450 molecules obtained after removal of duplicates
are used for virtual screening in the SARS-CoV-2 RdRp (U)
model. Ensemble docking was performed on the
SARS-CoV-2 RdRp (A, C and G) models, coupled with StoneWise's
proprietary AI-based prediction models to rank the activities of
the molecules, and the screening results are summarized in
electronic file for download.
References
[1] Sheahan, T.P., Sims, A.C.,
Leist, S.R. et al. Comparative therapeutic efficacy of
remdesivir and combination lopinavir, ritonavir, and interferon
beta against MERS-CoV. Nat Commun 11, 222
(2020).
[2] Tchesnokov, E.P.; Feng, J.Y.;
Porter, D.P.; Götte, M. Mechanism of Inhibition of Ebola Virus
RNA-Dependent RNA Polymerase by Remdesivir. Viruses 11,
326 (2019).
[3] Wang, M., Cao, R., Zhang,
L. et al. Remdesivir and chloroquine effectively inhibit
the recently emerged novel coronavirus (COVID-19) in
vitro. Cell Res (2020).
[4]
https://blast.ncbi.nlm.nih.gov
[5] Kirchdoerfer, R.N., Ward, A.B.
Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8
co-factors. Nat Commun 10, 2342
(2019).
Data acquisition methods
The methods to acquire the related data and results generated in
this study are as follows:
(1) Structured data of RNA polymerase nucleoside
inhibitors
The downloaded data is available in the csv, xlsx and sdf
formats.
(2) Virtual screening of SARS-CoV-2 polymerase
nucleoside compounds and homologous modeling used in this study
The downloaded contents include:
1. SARS-CoV-2 and GS-5734 complex models
2. Docking results based on SARS-CoV-2-RdRp_GS-5734_complex.pdb
3. Ensemble docking results of other three base mutation models
4. GS-5734 and SARS-CoV-2 RdRp interaction diagram
Go to http://www.stonewise.cn/Report_en, and enter the structure
data and docking result download page.
Thank you for your interest and support, and look forward to
your valuable opinions. If you have any suggestion and/or
collaboration requests, please send email to bd@stonewise.cn.
StoneWise will get in touch with you as soon as possible.
About StoneWise:
StoneWise, founded in 2018, is a technology company committed to
accelerating novel drug discovery with artificial intelligence. We
intend to use AI technology and innovation to lead a paradigm shift
in Drug discovery for the pharmaceutical industry. Our goal is to
replace the previous single-engine drug R&D focusing onexperts
based model with the new twin-engine drug R&D model with
advanced AI technology and expert system. Our platform is designed
by cutting-edge technologies such as artificial intelligence and
microfluidics, integrated with computational chemistry,
computational biology, pharmacology and clinical medicine. The
Platform provides pharmaceutical companies with integrated
solutions. These solutions include a vast range of tools such as
medical knowledge graph, the discovery of priviledged scaffolds,
molecular generation and design, as well as predicting reaction
products and planning path synthesis. Using this platform,
StoneWise hopes to enhancing the efficiency and success rate of
early stage drug discovery.
View original content to download
multimedia:http://www.prnewswire.com/news-releases/stonewise-ai-driven-drug-discovery-platform-investigation-and-repurpose-of-nucleoside-based-rna-polymerase-inhibitors-and-their-potential-use-in-covid-19-infection-treatment-301008336.html
SOURCE StoneWise